Benzothiadiazine compounds

Abstract

The invention relates to compounds of formula (I): wherein: R 1 represents alkyl substituted by one or more halogen atoms, R 2 represents hydrogen, halogen or hydroxy, R 3 represents unsubstituted or substituted aryl, their isomers, and also addition salts thereof. and medicinal products containing the same which are useful in treating or preventing disorders associated with AMPA flux.

1. A compound selected from those of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  represents linear or branched (C 1 -C 6 )alkyl substituted by one or more halogen atoms, 
 R 2  represents hydrogen, halogen or hydroxy, 
 R 3  represents unsubstituted aryl or aryl substituted by one or more identical or different groups selected from:
 linear or branched (C 1 -C 6 )alkyl; linear or branched (C 1 -C 6 )alkoxy; linear or branched (C 1 -C 6 )polyhaloalkyl; halogens; linear or branched (C 1 -C 6 )alkoxy-carbonyl; linear or branched (C 1 -C 6 )alkylthio; carboxy; linear or branched (C 1 -C 6 )acyl; linear or branched (C 1 -C 6 )polyhaloalkoxy; hydroxy; cyano; nitro; amidino, optionally substituted by one or two identical or different groups selected from linear or branched (C 1 -C 6 )alkyl, hydroxy, linear or branched (C 1 -C 6 )alkoxy and 
 
 
       
         
           
           
               
               
           
         
       
       amino, optionally substituted by one or two linear or branched (C 1 -C 6 )alkyl; aminocarbonyl, optionally substituted by one or two linear or branched (C 1 -C 6 )alkyl; benzyloxy; (C 1 -C 6 )alkylsulphonylamino, optionally substituted on the nitrogen by linear or branched (C 1 -C 6 )alkyl; trifluoromethylsulphonylamino; a heterocyclic group; and linear or branched (C 1 -C 6 )alkyl substituted by one or more identical or different groups selected from halogen, linear or branched (C 1 -C 6 )alkyl, NR 4 R 5 , S(O) n R 6 , OR 7 , amidino, optionally substituted by one or two identical or different groups selected from linear or branched (C 1 -C 6 )alkyl, hydroxy, linear or branched (C 1 -C 6 )alkoxy and 
       
         
           
           
               
               
           
         
       
       and a heterocyclic group, wherein:
 R 4  represents hydrogen, linear or branched (C 1 -C 6 )alkyl, S(O) p R 8 , COR 9  or P(O)(OR 10 )(OR 11 ), 
 R 5  represents hydrogen, linear or branched (C 1 -C 6 )alkyl, 
 or R 4  and R 5 , together with the nitrogen atom carrying them, form a heterocyclic group, 
 R 6 , R 8 , R 9 , R 10 , R 11  and R 12 , which may be the same or different, each represent hydrogen or linear or branched (C 1 -C 6 )alkyl optionally substituted by one or more halogen atoms; aryl-(C 1 -C 6 )alkyl wherein the alkyl moiety is linear or branched; or aryl, 
 R 7  represents linear or branched (C 1 -C 6 )alkyl or linear or branched (C 1 -C 6 )acyl, n and p, which may be the same or different, each represent 0, 1 or 2, its enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 
 
     
     
       2. A compound of  claim 1 , wherein R 1  represents haloethyl. 
     
     
       3. A compound of  claim 1 , wherein R 2  represents hydrogen. 
     
     
       4. A compound of  claim 1 , wherein R 3  represents unsubstituted phenyl. 
     
     
       5. A compound of  claim 1 , wherein R 3  represents phenyl substituted by amidino, hydroxyamidino, alkoxy, alkylsulphonylamino, optionally substituted on the nitrogen by alkyl, or alkyl substituted by amidino, hydroxyamidino, OR 7 , NH(SO) p R 8  or NHCOR 9 . 
     
     
       6. A compound of  claim 1 , which is selected from:
 N-(4-{[4-(2-fluoroethyl)-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-yl]oxy}benzyl)methanesulphonamide and 
 N-(4-{[4-(2-chloroethyl)-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-yl]oxy}benzyl)methanesulphonamide, and addition salts thereof with a pharmaceutically-acceptable acid or base. 
 
     
     
       7. A process for the synthesis of a compound selected from those of formula (I) of  claim 1 , comprising reaction of a compound selected from those of formula (VIII): 
       
         
           
           
               
               
           
         
       
       wherein R 1  represents linear or branched (C 1 -C 6 ) alkyl substituted by one or more halogen atoms and R 2  represents hydrogen, halogen or hydroxyl, with a compound selected from those of formula (V):
   R 3 —B(OH) 2   (V), 
 
       wherein
 R 3  represents unsubstituted aryl or aryl substituted by one or more identical or different groups selected from: 
 linear or branched (C 1 -C 6 )alkyl; linear or branched (C 1 -C 6 )alkoxy; linear or branched (C 1 -C 6 )polyhaloalkyl; halogens; linear or branched (C 1 -C 6 )alkoxy-carbonyl; linear or branched (C 1 -C 6 )alkylthio; carboxy; linear or branched (C 1 -C 6 )acyl; linear or branched (C 1 -C 6 )polyhaloalkoxy; hydroxy; cyano; nitro; amidino, optionally substituted by one or two identical or different groups selected from linear or branched (C 1 -C 6 )alkyl, hydroxy, linear or branched (C 1 -C 6 )alkoxy and 
 
       
         
           
           
               
               
           
         
       
       amino, optionally substituted by one or two linear or branched (C 1 -C 6 )alkyl; aminocarbonyl, optionally substituted by one or two linear or branched (C 1 -C 6 )alkyl; benzyloxy; (C 1 -C 6 )alkylsulphonylamino, optionally substituted on the nitrogen by linear or branched (C 1 -C 6 )alkyl; trifluoromethylsulphonylamino; a heterocyclic group ; and linear or branched (C 1 -C 6 )alkyl substituted by one or more identical or different groups selected from halogen, linear or branched (C 1 -C 6 )alkyl, NR 4 R 5 , S(O) n R 6 ,OR 7 , amidino, optionally substituted by one or two identical or different groups selected from linear or branched (C 1 -C 6 )alkyl, hydroxy, linear or branched (C 1 -C 6 )alkoxy and 
       
         
           
           
               
               
           
         
       
       and a heterocyclic group, wherein:
 R 4  represents hydrogen, linear or branched (C 1 -C 6 )alkyl, S(O) p R 8 ,COR 9  or P(O)(OR 10 )(OR 11 ), 
 R 5  represents hydrogen, linear or branched (C 1 -C 6 )alkyl, 
 or R 4  and R 5 , together with the nitrogen atom carrying them, form a heterocyclic group, 
 R 6 , R 8 , R 9 , R 10 , R 11  and R 12 , which may be the same or different, each represent hydrogen or linear or branched (C 1 -C 6 )alkyl optionally substituted by one or more halogen atoms; aryl-(C 1 -C 6 )alkyl wherein the alkyl moiety is linear or branched; or aryl, 
 R 7  represents linear or branched (C 1 -C 6 )alkyl or linear or branched (C 1 -C 6 )acyl, and n and p, which may be the same or different, each represent 0, 1 or 2, 
 
       to yield a compound selected from those of formula (I), which compound may be further purified, and which compound may be converted, if desired, into an addition salt thereof with a pharmaceutically acceptable acid. 
     
     
       8. A process for the synthesis of a compound selected from those of formula (I) of  claim 1 , comprising reaction of a compound selected from those of formula (IX): 
       
         
           
           
               
               
           
         
       
       wherein X represents a fluorine, chlorine, bromine or iodine atom, with a compound selected from those of formula (V):
   R 3 —B(OH) 2   (V), 
 
       wherein
 R 3  represents unsubstituted aryl or aryl substituted by one or more identical or different groups selected from: 
 linear or branched (C 1 -C 6 )alkyl; linear or branched (C 1 -C 6 )alkoxy; linear or branched (C 1 -C 6 )polyhaloalkyl; halogens; linear or branched (C 1 -C 6 )alkoxy-carbonyl; linear or branched (C 1 -C 6 )alkylthio; carboxy; linear or branched (C 1 -C 6 )acyl; linear or branched (C 1 -C 6 )polyhaloalkoxy; hydroxy; cyano; nitro; amidino, optionally substituted by one or two identical or different groups selected from linear or branched (C 1 -C 6 )alkyl, hydroxy, linear or branched (C 1 -C 6 )alkoxy and 
 
       
         
           
           
               
               
           
         
       
       amino, optionally substituted by one or two linear or branched (C 1 -C 6 )alkyl; aminocarbonyl, optionally substituted by one or two linear or branched (C 1 -C 6 )alkyl; benzyloxy; (C 1 -C 6 )alkylsulphonylamino, optionally substituted on the nitrogen by linear or branched (C 1 -C 6 )alkyl; trifluoromethylsulphonylamino; a heterocyclic group ; and linear or branched (C 1 -C 6 )alkyl substituted by one or more identical or different groups selected from halogen, linear or branched (C 1 -C 6 )alkyl, NR 4 R 5 , S(O) n R 6 ,OR 7 , amidino, optionally substituted by one or two identical or different groups selected from linear or branched (C 1 -C 6 ) alkyl, hydroxy, linear or branched (C 1 -C 6 )alkoxy and 
       
         
           
           
               
               
           
         
       
       and a heterocyclic group, wherein:
 R 4  represents hydrogen, linear or branched (C 1 -C 6 )alkyl, S(O) p R 8 ,COR 9  or P(O)(OR 10 )(OR 11 ), 
 R 5  represents hydrogen, linear or branched (C 1 -C 6 )alkyl, 
 or R 4  and R 5 , together with the nitrogen atom carrying them, form a heterocyclic group, 
 R 6 , R 8 , R 9 , R 10 , R 11  and R 12 , which may be the same or different, each represent hydrogen or linear or branched (C 1 -C 6 )alkyl optionally substituted by one or more halogen atoms; aryl-(C 1 -C 6 )alkyl wherein the alkyl moiety is linear or branched; or aryl, 
 R 7  represents linear or branched (C 1 -C 6 )alkyl or linear or branched (C 1 -C 6 )acyl, and n and p, which may be the same or different, each represent 0, 1 or 2, 
 
       to yield a compound selected from those of formula (I), which compound may be further purified, and which compound may be converted, if desired, into an addition salt thereof with a pharmaceutically acceptable acid. 
     
     
       9. A pharmaceutical composition comprising as active principle an effective amount of a compound of  claim 1 , together with one or more pharmaceutically-acceptable excipients or vehicules. 
     
     
       10. A method for treating a living animal body, including a human, afflicted with a condition selected from anxiety and depression, comprising the step of administering to the living animal body, including a human, an amount of a compound of  claim 1 , which is effective for alleviation of the condition.